Process for preparation of substituted amino alcohols

ABSTRACT

There is provided a process for the preparation of substituted amino alcohols HO—(CH 2 ) n —NR 1 R 2  from haloalcohols HO—(CH 2 ) n —X, where X is Cl, Br or I, by reaction with an amine HNR 1 R 2 , in water as solvent at a temperature range of about 20° C. to about 90° C. optionally in the presence of a catalytic amount of an iodide source metal iodides. The haloalcohols are useful in the preparation of 6-[(substituted)phenyl]-triazolopyrimidine compounds which are useful in the treatment of cancer.

This application claims priority from copending provisional applicationNo. 60/527,930, filed Dec. 8, 2003, the entire disclosure of which ishereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a process for the preparation ofsubstituted aminoalcohols which are useful in the preparation of tubulininhibitors which are useful in the treatment of cancer.

BACKGROUND OF THE INVENTION

There is still a need in the art for cytotoxic agents for use in cancertherapy. In particular, there is a need for cytotoxic agents whichinhibit or treat the growth of tumors which have an effect similar topaclitaxel and interfere with the process of microtubule formation.Additionally, there is a need in the art for agents which acceleratetubulin polymerization and stabilize the assembled microtubules.

Described in copending case Docket No. AM 101270, application No.60/505,544, filed Sep. 24, 2003 is a series of6-[(substituted)phenyl]-triazolopyrimidine compounds having thestructural formula

which are microtubule inhibitors and useful in the treatment of cancer.

Useful in the preparation of the above described6-[(substituted)phenyl]-triazolopyrimidine compounds are a series ofsubstituted amino alcohols of the formula HO—(CH₂)_(n)—NR¹R².

Described by Kabalka, George W.; Li, Nan-Sheng; and Pace, R. David,Synthetic Communications (1995), 25(14), 2135-43 is the preparation ofamino alcohols by the N-t-butoxycarbonyl protection of primary andsecondary amines via a hydroboration-oxidn reaction sequence.

Disclosed by Artyushin, O. I.; Petrovskii, P. V.; Mastryukova, T. A.;Kabachnik, M. I. Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya(1991), (9), 2154-7 is the simple synthesis of3-(alkylamino)-1-propanols by condensing for example NH₂(CH₂)₃OH withClCO₂Me in CH₂Cl₂ containing Na₂CO₃ which gave MeNH(CH₂)₃OH in 37%yield.

A. Parkkinen et al, Journal of Physical Organic Chemistry, (1991), 4(1),53-7 describes the hydrolytic decomposition of methyltetrahydrooxazinesto afford for example MeNH(CH₂)₃OH.

Described by Powell, John; James, Nadine; Smith, Stuart J., Synthesis(1986), (4), 338-40 is the preparation of MeNH(CH₂)₃OH by the lithiumaluminum hydride reduction of formamide HC(O)NH(CH₂)₃OH in the presenceof triethanolamine.

Kashima, Choji; Harada, Kazuo; Omote, Yoshimori, Canadian Journal ofChemistry (1985), 63(2), 288-90 describe the synthetic procedures wherein the presence of NaH, the methylation of H₂NCH₂CH₂OH by Me₂SO₄ in THFgave mainly H₂NCH₂CH₂OMe, MeNHCH₂CH₂OMe, and Me₂NCH₂CH₂OMe, whereas withLiH or CaH₂ the products were MeNHCH₂CH₂OH and Me₂NCH₂CH₂OH. Similarresults were obtained with H₂N(CH₂)₃OH to give MeHN(CH₂)₃OH.

Described by Felfoldi, K.; Laszlavik, M.; Bartok, M.; Karpati, E. ActaPhysica et Chemica (1980), 26(3-4), 163-9 is the preparation of numerouscompounds which include for example MeHN(CH₂)₃OH by reaction ofCl(CH₂)₃OH with methylamine in ethanol in an autoclave in 55% yield.However, the preparation method produces a flammable solvent and so isnot sufficient to prepare the substituted amino alcohols and inparticular, 3-methylamino-propan-1-ol.

Katritzky, Alan R.; Baker, Victor J.; Brito-Palma, Fernando M. S.Journal of the Chemical Society, Perkin Transactions 2: Physical OrganicChemistry (1972-1999) (1980), (11), 1739-45 describe the preparation forexample of MeHN(CH₂)₃OH by reduction of C₂H₅OC(O)(CH₂)₂NHMe with lithiumaluminum hydride in 56% yield.

Described by Jourdain, F.; Pommelet, J. C.; Tetrahedron Lett.; 35; 10;1994; 1545-1548, is the preparation of amino alcohols in which thechloroalcohols are reacted with an excess of amine in the presence ofethanol or aniline in toluene.

S. D. Goldberg; and W. F. Whitmore; J. Amer. Chem. Soc.; 59; 1937;2280-2282 describe the preparation of monoalkylaminopropanols whereinthe aminopropanol is reacted with trimethylene oxide made fromtrimethylene bromohydrin and 50% sodium hydroxide. However, the reactionwas effected by the action of trimethyleneoxide and trimethylenebromohydrin on the aminopropanol.

Described by S. Searles and V. P. Gregory; J. Amer. Chem. Soc.; 76;1954; 2789-2790 is the preparation, for example, wherein3-methylamino-1-propanol is formed by reaction of a 25% aqueous solutionof methylamine and trimethylene oxide in an autoclave at 150° C. for 12hours and then collecting the product by distillation.

Kurihara et al.; YKKZAJ; Yakugaku Zasshi; 74; 1954; 763; Chem. Abstr.;1955; 11646 describe the preparation of alkylaminopropanols wherein amixture of sodium, ammonium acetate, allyl alcohol and alkylamine arereacted in an autoclave at 130-150° C. for 7 hours. Prepared using thedescribed conditions is for example 3-methylamino-1-propanol.

Described by Cherbuliez, E. et al.; HCACAV; Helv. Chim. Acta; FR; 50;1967; 331-346 is the alkylation for example of amino-3-propanol-1 withmethyl iodide and the product 3-methylamino-propan-1-ol is purified bychromatography.

While the above described processes may be used to prepare substitutedamino alcohols there is a need for a simpler process which can be usedfor larger scale preparations.

SUMMARY OF THE INVENTION

The present invention provides a process for producing a series ofsubstituted amino alcohols of the formula HO—(CH₂)_(n)—NR¹R² wherein R¹and R² are each independently H or C₁-C₃ alkyl; or

-   R¹ and R² when optionally taken together with the nitrogen atom to    which each is attached form a 4 to 6 membered saturated heterocyclic    ring having 1-2 nitrogen atoms and 0-1 oxygen atoms or 0-1 sulfur    atoms, and optionally substituted with R³;-   R³ is C₁-C₃ alkyl; which comprises reacting a haloalcohol of the    formula X—(CH₂)_(n)—OH wherein X is bromo, chloro or iodo and n is    an integer of 2 to 7 with an amine HNR¹R² in an aqueous solution.

The described process may optionally contain an iodine source catalyst.

Definitions

The term base means an alkali metal hydroxide, alkali metal carbonate oralkali metal bicarbonate.

The term alkali metal hydroxide means lithium, potassium or sodiumhydroxide.

The term alkali metal carbonate means lithium, potassium or sodiumcarbonate.

The term alkali metal bicarbonate means lithium, potassium or sodiumbicarbonate.

The term alkali metal iodide means lithium, potassium or sodium iodide.

The term alkali metal hydride means lithium, potassium or sodiumhydride.

The term iodide source catalyst means alkali metal iodides ortetraalkylammonium iodides.

The term heterocyclic ring as used herein means a saturated heterocyclicring having 4 to 6 members having 1-2 nitrogen atoms, 0-1 oxygen atomsor 0-1 sulfur atoms optionally substituted with C₁-C₃ alkyl.Non-limiting representative examples include: morpholine, piperidine,pyrrolidine, piperazine, azetidine and N-methyl-piperazine.

The term alkyl means a straight or branched alkyl moiety of 1 to 3carbon atoms.

The term organic solvent means a solvent selected from the groupmethanol, ethanol, isopropanol, ethyl acetate, acetonitrile,tetrahydrofuran, diethylether, 1,4-dioxane, toluene and dichloromethane.

Dicarboxylic acid salts include the succinate or fumarate salt.

DETAILED DESCRIPTION OF THE INVENTION

A process for the preparation of a substituted amino alcohol of theformula HO—(CH₂)_(n)—NR¹R² wherein R¹ and R² are each independently H orC₁-C₃ alkyl; or R¹ and R² when optionally taken together with thenitrogen atom to which each is attached form a 4 to 6 membered saturatedheterocyclic ring having 1-2 nitrogen atoms and 0-1 oxygen atoms or 0-1sulfur atoms, and optionally substituted with R³; n is an integer of 2to 7; R³ is C₁-C₃ alkyl; comprising the reaction of a haloalcohol of theformula HO—(CH₂)_(n)—X, where X is Cl, Br or I, with an amine HNR¹R², inwater as solvent at a temperature range of about 20° C. to about 90° C.

Optionally the preparation of substituted amino alcohols of the formulaHO—(CH₂)_(n)—NR¹R² is in the presence of a catalytic amount of an iodidesource catalyst which includes alkali metal iodides ortetraalkylammonium iodides.

The preferred iodide source catalysts are alkali metal iodides and themost preferred is sodium and potassium iodide.

An embodiment of this process is wherein the optional amount of aniodide source catalyst used is the catalytic amount in the range ofabout 1 mole % to about 100 mole %. A preferred range is about 2 mole %to about 10 mole %. The most preferred catalytic amount is about 5 mole%.

Another embodiment of this process is wherein the mole ratio ofhaloalcohol to amine is in the range of about 1:1 to about 1:15. Apreferred mole ratio of haloalcohol to amine is in the range of about1:2 to about 1:8. The most preferred mole ratio of haloalcohol to amineis about 1:4.

The process may be carried out at a temperature range of about 15° C. toabout 90° C. A preferred temperature range is about 20° C. to about 50°C. The most preferred temperature is about 25° C.

The process may be carried out in the range of about 8 h to about 72 h.A preferred time range is about 10 h to about 24 h. The most preferredtime for the process to be carried out is about 15 h.

A preferred embodiment is where n is 2 to 4.

A particularly preferred embodiment is where n is 3.

An embodiment of this process is where R¹ and R² are each independentlyH or C₁-C₃ alkyl.

An embodiment of this process is where R¹ is H and R² is methyl.

An embodiment of this process is where X is Cl.

A process for the preparation of the aminoalcohol of the formula:HO—(CH₂)_(n)—NR¹R²wherein:

-   R¹ and R² are each independently H or C₁-C₃ alkyl; or-   R¹ and R² when optionally taken together with the nitrogen atom to    which each is attached form a 4 to 6 membered saturated heterocyclic    ring having 1-2 nitrogen atoms and 0-1 oxygen atoms or 0-1 sulfur    atoms, and optionally substituted with R³;-   n is an integer of 2 to 7; R³ is C₁-C₃ alkyl;    comprising the steps of:    -   a. reacting a haloalcohol of the formula HO—(CH₂)_(n)—X, where X        is Cl, Br or I, with an amine HNR¹R², in water to form an        aminoalcohol of the formula HO—(CH₂)_(n)—NR¹R²;    -   b. concentrating;    -   c. adding a base;    -   d. concentrating;    -   e. extracting with organic solvent;    -   f. filtering;    -   g. concentrating to a residue and collecting the product.

Optionally the residue collected may be collected and purified bydistillation.

The process may optionally include an iodide source catalyst.

Additionally, provided is a process for the preparation of a6-[(substituted)phenyl]-triazolopyrimidine of the formula

wherein:

-   R¹ and R² are each independently H or C₁-C₃ alkyl; or-   R¹ and R² when optionally taken together with the nitrogen atom to    which each is attached form a 4 to 6 membered saturated heterocyclic    ring having 1-2 nitrogen atoms and 0-1 oxygen atoms or 0-1 sulfur    atoms, and optionally substituted with R³;-   R⁵ is CF₃ or C₂F₅;-   R⁴ is H or C₁-C₃ alkyl;-   R³ is C₁-C₃ alkyl;-   n is an integer of 2 to 4;-   X is Cl or Br;    or a pharmaceutically acceptable dicarboxylic acid salt or hydrate    thereof    -   which comprises:    -   a. reacting a haloalcohol of the formula HO—(CH₂)_(n)—X, where X        is Cl, Br or I, with an amine HNR¹R², in water to form an        aminoalcohol of the formula HO—(CH₂)_(n)—NR¹, R²;    -   b. concentrating;    -   c. adding a base;    -   d. concentrating;    -   e. extracting with organic solvent;    -   f. filtering;    -   g. concentrating to a residue and collecting the aminoalcohol of        the formula HO—(CH₂)_(n)—NR¹, R²;    -   h. reacting the aminoalcohol HO—(CH₂)_(n)—NR¹R² with an alkali        metal hydride for about 30 minutes in tetrahydrofuran at about        10 to 40° C., adding the amine product        and heating to about 60° C. for about 12 to 20 h to obtain the        6-[(substituted)phenyl]-triazolopyrimidine product    -   i. reacting the 6-[(substituted)phenyl]-triazolopyrimidine        product with a dicarboxylic acid of the formula    -   wherein the dashed line is an optional bond, in t-butylmethyl        ether to obtain the 6-[(substituted)phenyl]-triazolopyrimidine        product dicarboxylic acid salt    -   j. optionally treating the        6-[(substituted)phenyl]-triazolopyrimidine product dicarboxylic        acid salt with water to obtain the        6-[(substituted)phenyl]-triazolopyrimidine as the hydrated salt.

The described process may optionally include an iodide source catalyst.

Preferably the dicarboxylic acid salt is the succinic acid salt and morepreferably as the anhydrous salt is treated with a saturated atmosphereof (80-100%) relative humidity of water to form the hydrated salt and inparticular the dihydrated salt.

Preferred bases include alkali metal hydroxide, alkali metal carbonateor alkali metal bicarbonate.

More preferred bases are alkali metal carbonates.

A particularly preferred base is potassium carbonate.

Preferred organic solvents include methyl alcohol, isopropyl alcohol orethyl acetate.

The following examples are presented to illustrate certain embodimentsof the present invention, but should not be construed as limiting thescope of this invention.

EXAMPLE 1

In a 3 L flask, 3-chloro-1-propanol (50.0 g, 0.53 mol, 98%, AldrichC4,640-3) is dissolved in methylamine solution (1 L, 40 wt. % in water,Aldrich 42,646-6) and heated to reflux for 3 days. The reaction iscooled to room temperature and the solvent is reduced in vacuo to about150 mL. To the reaction mixture, potassium carbonate (50 g) is added andthe remainder of solvent is removed. The residue is suspended inmethanol (200 mL) and filtered through a plug of silica gel (200 g). Theplug is washed with methanol (2×100 mL), the organic layers arecombined, and the solvents are removed to give an orange oil. The oil isdistilled at about 1-2 mm Hg from room temperature to 60° C. with an oilbath and a distillation trap. The distillation afforded3-methylamino-propan-1-ol as a clear, colorless liquid (22.0 g), BP165-167° C. (760 torr), C₄H₁₁NO, MW 89.14.

EXAMPLE 2

A mixture of 30 g of sodium iodide, 500 g of 3-chloro-1-propanol and4000 mL of methylamine solution (40 wt. % in water, Aldrich 42,646-6) isstirred at room temperature for about 17 h. The solvent is reduced invacuo to about 700-800 mL. To the reaction mixture, potassium carbonate(500 g) is added and the remainder of water is removed to a residuewhich is distilled with toluene to afford a residue. The residue issuspended in methanol (2000 mL), filtered and the cake washed withmethanol (2×1000 mL). The methanol layers are combined, and the solventsare removed to give an oil. The oil is distilled to afford3-methylamino-propan-1-ol as a clear, colorless liquid (352.0 g), BP90-95° C. (8 mm), C₄H₁₁NO, MW 89.14.

1. A process for the preparation of a substituted amino alcohol of theformula HO—(CH₂)_(n)—NR¹R² wherein R¹ and R² are each independently H orC₁-C₃ alkyl; or R¹ and R² when optionally taken together with thenitrogen atom to which each is attached form a 4 to 6 membered saturatedheterocyclic ring having 1-2 nitrogen atoms and 0-1 oxygen atoms or 0-1sulfur atoms, and optionally substituted with R³; n is an integer of 2to 7; R³ is C₁-C₃ alkyl; comprising the reaction of a haloalcohol of theformula HO—(CH₂)_(n)—X, where X is Cl, Br or I, with an amine HNR¹R², inwater as solvent at a temperature range of about 20° C. to about 90° C.2. The process of claim 1 further comprising an iodide source catalyst.3. The process of claim 2 wherein the iodide source catalyst is presentin a catalytic amount.
 4. The process according to claim 3 wherein theiodide source catalyst is an alkali metal iodide or a tetraalkylammoniumiodide.
 5. The process according to claim 4 wherein the alkali metaliodide is sodium or potassium iodide.
 6. The process according to claim3 wherein the catalytic amount of iodide source catalyst is present inabout 1 mole % to about 100 mole %.
 7. The process according to claim 6wherein the catalytic amount of iodide source catalyst is present inabout 5 mole % to 10 mole %.
 8. The process according to claim 7 whereinthe iodide source catalyst is present in about 5 mole %.
 9. The processaccording to claim 8 wherein the temperature range is about 20 to about50° C.
 10. The process according to claim 9 wherein the temperature isabout 25° C.
 11. The process according to claim 1 wherein X is Cl. 12.The process according to claim 1 wherein n is 2 to
 4. 13. The processaccording to claim 12 wherein n is
 3. 14. The process according to claim1 wherein the mole ratio of haloalcohol to amine is in the range ofabout 1:1 to about 1:15.
 15. The process according to claim 14 whereinthe mole ratio of haloalcohol to amine is in the range of about 1.2 toabout 1.8.
 16. The process according to claim 15 wherein the mole ratioof haloalcohol to amine is about 1:4.
 17. The process according to claim1 wherein R¹ and R² are each independently H or C₁-C₃ alkyl.
 18. Theprocess according to claim 17 wherein R¹ is H and R² is methyl.
 19. Aprocess for the preparation of an aminoalcohol of the formula:HO—(CH₂)_(n)—NR¹R² wherein: R¹ and R² are each independently H or C₁-C₃alkyl; n is an integer of 2 to 7; comprising the steps of: a. reacting ahaloalcohol of the formula HO—(CH₂)_(n)—X, where X is Cl, Br or I, withan amine HNR¹R², in water at about 20° C. to about 90° C. to form anaminoalcohol of the formula HO—(CH₂)_(n)—NR¹R²; b. concentrating; c.adding a base; d. concentrating; e. extracting with organic solvent; f.filtering; g. concentrating to a residue and collecting the product. 20.The process of claim 19 further comprising an iodide source catalyst instep a of said process.
 21. The process of claim 20 wherein an iodidesource catalyst is present in a catalytic amount.
 22. The processaccording to claim 21 wherein the iodide source catalyst is an alkalimetal iodide or a tetraalkylammonium iodide.
 23. The process accordingto claim 22 wherein the alkali metal iodide is sodium or potassiumiodide.
 24. The process according to claim 21 wherein the catalyticamount of iodide source catalyst is present in about 1 mole % to about100 mole %.
 25. The process according to claim 24 wherein the catalyticamount of iodide source catalyst is present in about 5 mole % to 10 mole%.
 26. The process according to claim 25 wherein the iodide sourcecatalyst is present in about 5 mole %.
 27. The process according toclaim 19 wherein the temperature range is about 20 to about 50° C. 28.The process according to claim 27 wherein the temperature is about 25°C.
 29. The process according to claim 19 wherein X is Cl.
 30. Theprocess according to claim 19 wherein n is 2 to
 4. 31. The processaccording to claim 30 wherein n is
 3. 32. The process according to claim19 wherein the mole ratio of haloalcohol to amine is in the range ofabout 1:1 to about 1:15.
 33. The process according to claim 32 whereinthe mole ratio of haloalcohol to amine is in the range of about 1.2 toabout 1.8.
 34. The process according to claim 33 wherein the mole ratioof haloalcohol to amine is about 1:4.
 35. The process according to claim19 wherein R¹ and R² are each independently H or C₁-C₃ alkyl.
 36. Theprocess according to claim 35 wherein R¹ is H and R² is methyl.
 37. Theprocess according to claim 19 wherein the base is an alkali metalhydroxide, alkali metal carbonate or alkali metal bicarbonate.
 38. Theprocess according to claim 37 wherein the base is an alkali metalcarbonate.
 39. The process according to claim 38 wherein the alkalimetal carbonate is potassium carbonate.
 40. The process according toclaim 19 wherein the organic solvent is selected from the groupmethanol, ethanol, isopropanol, ethyl acetate, acetonitrile,tetrahydrofuran, diethylether, 1,4-dioxane, toluene and dichloromethane.41. The process according to claim 40 wherein the organic solvent ismethyl alcohol, isopropyl alcohol and ethyl acetate.
 42. A process forthe preparation of a 6-[(substituted)phenyl]-triazolopyrimidine of theformula

wherein: R¹ and R² are each independently H or C₁-C₃ alkyl; or R¹ and R²when optionally taken together with the nitrogen atom to which each isattached form a 4 to 6 membered saturated heterocyclic ring having 1-2nitrogen atoms and 0-1 oxygen atoms or 0-1 sulfur atoms, and optionallysubstituted with R³; R⁵ is CF₃ or C₂F₅; R⁴ is H or C₁-C₃ alkyl; R³ isC₁-C₃ alkyl; n is an integer of 2, 3, or 4; X is Cl or Br; or apharmaceutically acceptable dicarboxylic acid salt or hydrate thereofwhich comprises: a. reacting a haloalcohol of the formulaHO—(CH₂)_(n)—X, where X is Cl, Br or I, with an amine HNR¹R², in waterat about 20° C. to about 90° C. to form an aminoalcohol of the formulaHO—(CH₂)_(n)—NR¹R²; b. concentrating; c. adding a base; d.concentrating; e. extracting with organic solvent; f. filtering; g.concentrating to a residue and collecting the aminoalcohol of theformula HO—(CH₂)_(n)—NR¹R²; h. reacting the aminoalcoholHO—(CH₂)_(n)—NR¹R² with an alkali metal hydride for about 30 minutes intetrahydrofuran at about 10 to 40° C., adding the amine product

and heating to about 60° C. for about 12 to 20 h to obtain the6-[(substituted)phenyl]-triazolopyrimidine product

i. reacting the 6-[(substituted)phenyl]-triazolopyrimidine product witha dicarboxylic acid of the formula

wherein the dashed line is an optional bond, in t-butylmethyl ether toobtain the 6-[(substituted)phenyl]-triazolopyrimidine productdicarboxylic acid salt

j. optionally treating the 6-[(substituted)phenyl]-triazolopyrimidineproduct dicarboxylic acid salt with water to obtain the6-[(substituted)phenyl]-triazolopyrimidine as the hydrated salt.
 43. Theprocess according to claim 42, step j, wherein the dihydrate is formed.